Amajorissueinschizophrenia(SZ)istobaccosmoking,whichleadstolungcancer,poorqualityoflife, andnegativehealthoutcomes.Theadenosinesystemrepresentsanovelpharmacologicaltreatmenttarget, becauseadenosinemaycontributetobothpsychosisandsubstanceabusecomorbidityinSZ.AdenosineA2A receptorsformaheteromericcomplexwithdopamineD2receptorsinthebrainthatismutuallyinhibitory. AdenosineA2AagonistsreduceD2receptorsensitivity,whereasD2agonistsreduceA2Areceptorsensitivity. Thisisimportant,becauseincreasedD2receptorsensitivityunderliespsychosisinSZ.Thisapplicationcenters aroundarodentmodelofSZofD2sensitivity,withratsneonatallytreatedwiththedopamineD2/D3agonist quinpirole(neonatalquinpiroletreatment,NQ).NQtreatmentresultsinincreasedD2receptorsensitivity throughouttheanimal?slifetimewithoutalteringD2density,consistentwithSZ.Insum,preliminarydata revealedthatNQenhancedtherewardingassociativeaspectsofnicotineaswellasthebrain-derived neurotrophicfactor(BDNF)andglialcell-linederivedneurotrophicfactor(GDNF)responsetonicotine.These responseswerereducedbyadenosineA2AagonistCGS21680aswellastheantipsychoticclozapine.In addition,NQtreatmenthasbeenshowntoresultinauditorysensorimotorgatingdeficits,abehavioralhallmark ofSZ.TheoverallhypothesisisthatNQ-inducedenhancementofthebehavioralresponsetonicotineand auditorysensorimotorgatingdeficitscanbemitigatedbyadenosineA2Aactivationincombinationwith clozapineandchangesinBDNFandGDNFsignalingcascades.Aim1willanalyzepotentialsynergistic effectsoftheA2AreceptoragonistCGS21680andclozapineonnicotineCPPandauditory sensorimotorgatinginadolescentNQ-treatedmaleandfemalerats.Aim1awillthentestthehypothesis thatCGS21680combinedwithclozapinewillmosteffectivelyreduceNQ-inducedenhancementofnicotine CPP.Aim1bwilltestthehypothesisthatCGS21680alonewillreduce,andincombinationwithclozapinewill alleviate,sensorimotorgatingdeficitsproducedbyNQ,showingthatadenosineA2Areceptoractivationis effectivetotreatbothnicotineabuseandpsychosis-likesymptoms.Aim2willinvestigatewhetherCGS 21680willreduceenhanceddopamineandglutamatereleaseintheNAccinadolescentNQ-treated maleandfemalerats.WehypothesizethatA2Areceptoractivationviareversemicrodialysisinfusionintothe brainwillreduceenhanceddopamineandglutamatereleaseinresponsetonicotineinNQ-treatedratstested inadolescence.Aim3willanalyzecommondownstreamneurobiologicaltargetsofBDNFandGDNFin NQ-treatedanimalsadministeredCGS21680inadolescence.WehypothesizethatA2Areceptoractivation combinedwithclozapinewillmitigatethedownstreamresponseofproteinscommontoboththeBDNFand GDNFsignalingcascadesinthenucleusaccumbensandhippocampus,brainareasthatareimplicatedindrug addictionandpsychosisrespectively.